Secondary Logo

Journal Logo

Original Articles

Bamlanivimab for the Prevention of Hospitalizations and Emergency Department Visits in SARS-CoV-2–Positive Patients in a Regional Health Care System

Priest, David H. MD, MPH; Blanchette, Lisa M. PharmD, MHA; Hekman, Aliza L. MMS, PA-C; Maddikunta, Rahul MS; Burleson, Paula E. BSBA

Author Information
Infectious Diseases in Clinical Practice: March 2022 - Volume 30 - Issue 2 - p 1-4
doi: 10.1097/IPC.0000000000001130
  • Open

Abstract

The COVID-19 pandemic caused by SARS-CoV-2 has had a devastating impact on the health of communities around the world, as well as the global economy.1,2 In response, several therapeutic interventions have been developed and evaluated, including virus neutralizing monoclonal antibodies.3,4 These antibodies are isolated from the blood of recovered patients after infection with SARS-CoV-2 and offer passive immunity to those receiving the antibody therapies. One such agent is bamlanivimab (LY-CoV555; Lilly), a recombinant, neutralizing monoclonal antibody developed by the US Vaccine Research Center at the National Institute of Allergy and Infectious Diseases and AbCellera using their pandemic response platform.3 Bamlanivimab adheres to the binding domain of the spike protein found on SARS-CoV-2, thus preventing the attachment of the spike protein to the angiotensin-converting enzyme 2 receptor.5 Bamlanivimab was isolated from a blood sample taken from a patient infected with SARS-CoV-2 early in the pandemic and was selected from approximately 500 unique antibodies discovered after screening over 5 million antibody-producing cells found in that sample.3

Bamlanivimab was granted a Food and Drug Administration (FDA) Emergency Use Authorization (EUA) on November 10, 2020, for treatment of mild to moderate SARS-CoV-2 infection in adults and children 12 years and older after early studies demonstrated that bamlanivimab reduced SARS-CoV-2–related emergency room visits and hospital admissions in high-risk patients in the 28 days after treatment.6,7 No beneficial outcomes were identified among hospitalized patients infected with SARS-CoV-2.8 As such, EUA use criteria excluded patients hospitalized for SARS-CoV-2 infection. After the EUA was granted, a federal allocation program was used to distribute bamlanivimab to health care providers through state health departments based on the number of local cases and the severity of outbreaks.5 Subsequently, evaluation of bamlanivimab monotherapy as well as in combination with etesevimab (LY-CoV016) has occurred through ongoing clinical trials.9

As health care systems received allocations of bamlanivimab, significant challenges in the use of the agent had to be overcome. These challenges included, but were not limited to, identifying staff and facilities where bamlanivimab could be safely administered to patients with active SARs-CoV-2 infection without exposing team members or other patients, the ability to manage potential hypersensitivity reactions, educating health care providers on the appropriate use of the agent, as well as developing the operational means of ordering it, and managing patient expectations and eligibility criteria.10 On April 16, 2021, the FDA revoked the EUA for bamlanivimab citing reductions in viral susceptibility to bamlanivimab caused by virus variant substitutions and the lack of availability of testing technologies allowing clinicians to distinguish between SARS-CoV-2 variants.11 Despite the revocation of the EUA, lessons learned from the experience with bamlanivimab may still be relevant given that additional monoclonal antibody products remain available in the market.12

We report a retrospective, case-control study describing the outcomes of bamlanivimab use in a regional health care system during the COVID-19 pandemic under real world conditions during its EUA availability.

MATERIALS AND METHODS

This was a retrospective case-control study of patients receiving bamlanivimab and matched controls at Novant Health between October 2020 and March 2021. Novant Health is a regional health care system in the southeast United States composed of 15 inpatient medical centers and 674 ambulatory locations. Bamlanivimab was administered in 13 emergency department locations and 5 infusion centers. This project was part of a quality improvement review during the COVID-19 pandemic.

Patient Referral Process

Patients with a positive diagnostic SARS-CoV-2 viral test who met EUA criteria for bamlanivimab were identified by providers in the ambulatory care setting and referred to outpatient infusion centers for treatment or were identified and administered bamlanivimab in the emergency department setting. A bamlanivimab order set and therapy plan were created to improve ease of provider ordering. In addition, providers were educated on both the clinical utility and availability of bamlanivimab through a system-wide newsletter as well as through intranet resources. Patients could be scheduled at designated infusion center locations using the health system's usual infusion-referral process. Each day, appointment slots were specifically held open to accommodate referrals for patients needing COVID-19 monoclonal antibody treatment. When entering our health care facilities for infusion of bamlanivimab, patients known to be positive for SARS-CoV-2 were masked and escorted directly to infusion centers. Patients were placed in private rooms with enhanced respiratory precautions to include use of N95/PAPR in addition to gown, gloves, and eye protection by team members entering the room.

Data Collection and Statistical Analysis

Patients who received bamlanivimab were identified through structured electronical health record (EHR) relational database tables by the medication order date using Azure Data Studio. Patients in the treatment population received bamlanivimab between December 2020 and March 2021 and were identified by the medication order date and a medication status of completed.

Control population patients were identified by a positive diagnostic SARS CoV-2 viral test performed between October 2020 and March 2021, and no receipt of COVID-19 monoclonal antibody products noted.

Endpoints included all-cause inpatient admission (observation or inpatient status), all-cause emergency department visit and all-cause mortality. These endpoints were noted if occurring within 28 days of bamlanivimab infusion or within 28 days of a positive COVID-19 test in matched controls. Other data collected included: age, sex, body mass index (BMI), race, ethnicity, diagnosis of diabetes, and diagnosis of cancer. Patients with diagnoses of diabetes, or cancer, or BMI of 35 or greater, were identified if the condition was documented as an encounter diagnosis after January 1, 2020. High risk patients were defined as those 65 years or older, BMI of 35 or greater, diagnosis of diabetes mellitus or cancer.

Patients who received bamlanivimab were matched to the control population with an unbiased approach using 1:1 nearest neighbor matching with replacement. This method relies on propensity scores estimated with logistical regression to find the closest match based on age, sex, ethnicity, BMI, diabetes, cancer, and mortality. Patients were divided into 3 periods of a similar number of patients to compare end points at different times within the study period. Statistical analysis and propensity score matching were done using R-Language and RStudio Server.

RESULTS

A total of 758 patients were included in the study, 379 patients treated with bamlanivimab and matched with a control population of the same number. Baseline characteristics of the study population are included in Table 1. The population was 51% women. Thirty percent of patients were in the 70 to 79 years age group, followed by 25% in the 60 to 69 years age group. All-cause hospital admissions and emergency department visits were similar in both groups (21% and 20% among treatment and control populations, respectively). Neither overall nor among high-risk populations was any statistically significant difference identified in the prevention of emergency department visits or inpatient admission after administration of bamlanivimab (Table 2). In patients 65 years or older, there was an association with fewer emergency department visits and inpatient admissions (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.51–1.31) although it was not statistically significant (P = 0.43).

TABLE 1 - Baseline Characteristics
Characteristics Treatment Population (n = 379) Control Population (n = 379)
Age, n (%)
 Median, y
 Mean, y
 40–49 28 (7) 27 (7)
 50–59 63 (17) 62 (16)
 60–69 95 (25) 95 (25)
 70–79 115 (30) 116 (31)
 80–84 24 (6) 23 (6)
 85+ 26 (7) 28 (7)
 Other (under 40) 28 (7) 28 (7)
Sex
 Female 193 (51) 193 (51)
 Male 186 (49) 186 (49)
Race
 American Indian 2 (1) 1 (0)
 Asian 3 (1) 2 (1)
 Black 73 (19) 73 (19)
 White 292 (77) 293 (77)
 Other 9 (2) 10 (3)
Language
 English 371 (98) 370 (98)
 Spanish 7 (2) 6 (2)
 Other 1 (0) 3 (1)
BMI
 <35 253 (67) 256 (68)
 ≥35 126 (33) 123 (32)
Chronic conditions
 Diabetes 104 (27) 101 (27)
 Cancer 47 (12) 45 (12)
 All high risk* 333 (88) 333 (88)
Outcomes
 All-cause hospital revisit (28 d) 79 (21) 76 (20)
 All-cause mortality (30 d) 6 (2) 6 (2)
*High risk = ≥ 65 years, BMI ≥ 35, diabetes, or cancer.

TABLE 2 - Risk of Hospitalization or Emergency Department Visit for Bamlanivimab vs Matched Controls
Predictors OR (95% CI) P
Overall 1.05 (0.73–1.52) 0.86
 All high risk 1.04 (0.71–1.52) 0.93
 BMI ≥ 35 1.51 (0.75–3.13) 0.25
 Diabetes 1.02 (0.50–2.06) 1.00
 Cancer 1.22 (0.40–3.78) 0.80
 Age ≥65 y 0.82 (0.51–1.31) 0.43
Symptom onset, 0–3 d 1.79 (0.88–3.67) 0.15
 All high risk 1.87 (0.89–3.93) 0.14
 BMI ≥ 35 2.70 (0.72–10.1) 0.21
 Diabetes 1.49 (0.39–5.74) 0.74
 Cancer 2.92 (0.41–20.9) 0.37
 Age ≥65 y 1.12 (0.45–2.79) 1.00
Symptom onset, 4–7 d 0.83 (0.51–1.35) 0.53
  All high risk 0.79 (0.47–1.32) 0.43
 BMI ≥ 35 1.56 (0.61–3.95) 0.48
 Diabetes 0.95 (0.40–2.30) 1.00
 Cancer 1.00 (0.26–3.91) 1.00
 Age ≥65 0.56 (0.30–1.05) 0.08
Symptom onset, ≥8 d 1.08 (0.51–2.30) 1.00
 All high risk 1.08 (0.49–2.37) 1.00
 BMI ≥ 35 0.72 (0.17–2.96) 0.73
 Diabetes 0.76 (0.18–3.24) 1.00
 Cancer 0.42 (0.03–6.06) 1.00
 Age ≥65 y 1.44 (0.59–3.52) 0.50

In addition, no difference was seen based on timing of bamlanivimab infusion relative to disease symptom onset. The median time from symptom onset to bamlanivimab infusion was 6 days; 22.8% of patients received therapy within 3 days of symptom onset, 54.2% received therapy between 4 and 7 days from symptom onset, and 23.3% received therapy day 8 or later of symptom onset. Patients with a symptom duration of 0 to 3 days were more likely to receive bamlanivimab in the emergency department compared with the ambulatory setting (53.5% of infusions administered in ED among patients with symptom duration of 0–3 days). Those with symptom duration of 4 to 7 days received therapy in the emergency department 31.2% of the time and those with symptom during of 8+ days received therapy in the emergency department 28.4% of the time compared with the ambulatory setting. There was a trend toward increased likelihood of hospital admission or emergency department visit in high-risk patients (OR, 1.87; 95% CI, 0.89–3.93) who received bamlanivimab within 3 days of symptom onset; however, this was not statistically significant (P = 0.14). Those 65 years or older who received bamlanivimab in the 4 to 7 days after symptom onset appeared to have the most benefit (OR, 0.56; 95% CI, 0.30–1.05), although this was not statistically significant (P = 0.08). No statistically significant change in outcomes was noted early in the study versus later in the study period (Table 3). Patients who received bamlanivimab during the first time range had a higher likelihood of hospital admission or emergency department visit (OR, 1.16; 95% CI, 0.63–2.13) as compared with patients who received bamlanivimab during the most recent timeframe who had a lower likelihood of hospital admission or emergency department visit (OR, 0.82; 95% CI, 0.40–1.67; with P = 0.76 and P = 0.72, respectively).

TABLE 3 - Risk of Hospitalization or Emergency Department Visit for Bamlanivimab vs Matched Controls Over Time
Predictors OR (95% CI) P
Time range 1 (n = 110) (December 6, 2020 to January 22, 2021) 1.16 (0.63–2.13) 0.76
Time range 2 (n = 164) (January 23, 2021 to February 10, 2021) 1.13 (0.65–1.95) 0.78
Time range 3 (n = 105) (February 11, 2021 to March 14, 2021) 0.82 (0.40–1.67) 0.72

No mortality benefit was observed in this study with a 2% all-cause mortality rate in both treatment and control populations. No serious safety events were noted during the study.

DISCUSSION

As the COVID-19 pandemic continues to have a devastating impact on communities across the world, new therapeutic options are needed to care for patients infected with SARS-CoV-2. A variety of agents have been suggested as potential therapies, including monoclonal antibodies.3 Bamlanivimab is a monoclonal antibody that targets the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. It was isolated from an early case of COVID-19 and showed the highest affinity for SARS-CoV-2 among over 500 isolated antibodies evaluated.3 Interim analysis of data from the Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies trial suggested that bamlanivimab reduces the incidence of COVID-19–related hospitalization and emergency department visits in patients in the ambulatory setting, particularly those 65 years or older or those with a BMI of 35 or greater.7 It has not been found to improve clinical outcomes in hospitalized patients with SARS-CoV-2.8 Limited, early experience suggested that bamlanivimab may be beneficial in nonhospitalized, immunocompromised individuals or other high-risk patients, if given early in the clinical course.13,14

As the FDA approved bamlanivimab through an emergency use authorization, doses became widely available to health care systems via state allocation.6 Uptake in use of the agent was slow; however, as health care systems struggled with operationalizing the administration of bamlanivimab while also dealing with the need for mass testing programs for SARS-CoV-2, managing large numbers of inpatient admissions, and preventing spread of the infection to team members and patients.10 Administration of bamlanivimab required having a location where the drug could be safely administered via intravenous infusion to an individual with SARS-CoV-2 infection without risking exposure to noninfected patients. We identified 2 care settings within our health system to accommodate patients eligible for bamlanivimab infusions: (i) within the emergency department (bamlanivimab therapy was provided at 13 EDs) and (ii) through scheduled appointments at our outpatient infusion centers (bamlanivimab appointments were available at 5 outpatient infusion centers).

We report on a real world, rapid deployment of bamlanivimab for the treatment of SARS-CoV-2 after a broad emergency use authorization. In this retrospective, case-control study, we did not see any statistically significant benefit in the prevention of emergency department visits or inpatient admission after administration of bamlanivimab. Similarly, Gottlieb et al9 reported that there was not a statistically significant reduction in hospitalization or emergency department visits in patients who had received bamlanivimab monotherapy but did observe a reduction in those who received bamlanivimab and etesevimab combination therapy. Bamlanivimab monotherapy seemed to show some benefit in a small case series in solid organ transplant recipients where no progression of SARS-CoV-2 clinical disease that led to hospitalization was noted.13 In our study, among patients 65 years or older, there was an association with fewer emergency department visits and inpatient admissions although it was not statistically significant (P = 0.43).

Interestingly, when we examined the relationship between timing of administration related to symptom onset and outcomes, we found that those who received bamlanivimab within 3 days of symptom onset had a trend toward a higher likelihood of subsequent inpatient admission or emergency department visit than those who did not receive bamlanivimab (OR, 1.87; 95% CI, 0.89–3.93) but this was not statistically significant (P = 0.14). This ran contrary to the expected benefit that early administration of therapy would lead to improved outcomes. We speculate that patients who received therapy within 3 days of symptom onset may have been identified through selection bias as physicians may have chosen them for therapy based on a higher severity of symptoms or a higher number of clinical conditions or risk factors for poor SARS-CoV-2–related outcomes. These patients may have been more likely to require admission to the hospital regardless of preadmission treatment. In addition, patients who received therapy within 3 days of symptom onset were more like to receive bamlanivimab in the emergency department setting (53.5%) compared with those who had symptoms for 4 to 7 days (31.2%) and those with 8 or more days of symptoms (28.4%); thus, selecting outpatients who were already more clinically ill and who sought care in the emergency department. Patients who received therapy after having had symptoms for longer than 3 days were less clinically ill. We noticed, anecdotally, that when patients were less ill, there was less urgency in getting them to a location for bamlanivimab treatment. By the time these patients received therapy, it may have been given at a time when clinical recovery was already likely.

Of note, we did not observe any serious safety events during the study. No mortality benefit was observed with mortality rates in both groups of 2%.

After the completion of our study, the FDA revoked the EUA for bamlanivimab monotherapy.11 The EUA was revoked given the recognition that variant substitutions, E484K and L452R, resulted in significant reductions in susceptibility to bamlanivimab.11 These mutations in the SARS-CoV-2 spike RBD that allow the virus to escape monoclonal antibody binding have been increasingly described.15,16 Liu et al17 describe that, in vitro, the SARS-CoV-2 mutation E484K, found in the Beta variant (B.1.351) and the Gamma variant (P.1) alters the RBD with total loss of binding from bamlanivimab.

Strengths of our study included the large sample size and the examination of outcomes in real-world conditions faced by health care systems and providers during the pandemic. In addition, our 1:1 nearest neighbor matching with replacement using propensity score methodology matched control patients with treated patients using age, sex, ethnicity, BMI, diabetes, cancer, and mortality to limit bias.

In addition to the retrospective nature of the study, there are several other limitations. At the time of the study, we did not have the ability to detect mutations that might alter the effectiveness of monoclonal antibody therapy or even the ability to know if a particular patient had a SARS-CoV-2 variant that might carry a mutation that renders therapy less effective. This lack of diagnostic options for clinicians was also noted in the FDA's decision to revoke the bamlanivimab EUA.11 We also did not have a rigorous national, state, or community mutation monitoring program that would allow us to know the prevalence of SARS-CoV-2 variants in the communities in which we serve. In the future, more real time information on SARS-CoV-2 variants would aid in the selection of monoclonal therapies at the community and patient levels. The lack of bamlanivimab efficacy noted in our study could have been related to an unrecognized higher percentage of circulating mutant strains within our health care system footprint, although, we do not have reason to believe that was the case, particularly early in our bamlanivimab infusion program services when newer variants were uncommon in regional and national data. We did not observe higher efficacy of bamlanivimab therapy early in the study period compared with later periods, again suggesting that the lack of clinical benefit was not due to changes in the activity of SARS-CoV-2 variants within the communities we serve.

In this real-world study examining the benefits of bamlanivimab monotherapy for the prevention of hospital admission or emergency department visit in a regional health care system, we did not find clinical benefit. Our conclusion supports the recent revocation of the bamlanivimab monotherapy EUA by the FDA.

REFERENCES

1. Johns Hopkins University: Coronavirus Resource Center. Available at: https://coronavirus.jhu.edu. Accessed 30 March 2021.
2. International Monetary Fund. Available at: https://www.imf.org/external/pubs/ft/ar/2020/eng/downloads/imf-annual-report-2020.pdf. Accessed 30 March 2021.
3. Tuccori M, Ferraro S, Convertino I, et al. Anti-SARS-CoV-2 neutralizing monoclonal antibodies: clinical pipeline. MAbs. 2020;12(1):1854149. doi:10.1080/19420862.2020.1854149. PMID: 33319649.
4. Pallotta AM, Kim C, Gordon SM, et al. Monoclonal antibodies for treating COVID-19. Cleve Clin J Med. 2021. doi:10.3949/ccjm.88a.ccc074 Online ahead of print. PMID: 33597176.
5. An EUA for bamlanivimab - a monoclonal antibody for COVID-19. Med Lett Drugs Ther. 2020;62(1612):185–186.
6. Food and Drug Administration. Letter to Eli Lilly and Company. Available at: https://www.fda.gov/media/143602/download; 2020. Accessed 30 March 2021.
7. Chen P, Nirula A, Heller B, et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N Engl J Med. 2021;384(3):229–237. doi:10.1056/NEJMoa2029849.
8. Lundgren JD, Grund B, Barkauskas CE, et al; ACTIV-3/TICO LY-CoV555 Study Group. A neutralizing monoclonal antibody for hospitalized patients with Covid-19. N Engl J Med. 2021;384(10):905–914. doi:10.1056/NEJMoa2033130.
9. Gottlieb RL, Nirula A, Chen P, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2021;325(7):632–644.
10. McGinley L. Only one Covid-19 treatment is designed to keep people out of the hospital. Many overburdened hospitals are not offering it. The Washington Post. Available at: https://www.washingtonpost.com/health/2020/12/31/covid-monoclonal-antibodies-unused/; 2020. Accessed March 30, 2021.
11. Food and Drug Administration. Letter to Eli Lilly and Company. Available at: https://www.fda.gov/media/147629/download; 2021. Accessed April 29, 2021.
12. Kaplon H, Reichert JM. Antibodies to watch in 2021. MAbs. 2021;13(1):1860476. doi:10.1080/19420862.2020.1860476. PMID: 33459118.
13. Dhand A, Lobo SA, Wolfe K, et al. Bamlanivimab for treatment of COVID-19 in solid organ transplant recipients: early single-center experience. Clin Transpl. 2021;35:e14245. doi:10.1111/ctr.14245.
14. Tulledge-Scheitel S, Bell SJ, Larsen JJ, et al. A mobile unit overcomes the challenges to monoclonal antibody infusion for COVID-19 in skilled care facilities. J Am Geriatr Soc. 2021;69:868–873. doi:10.1111/jgs.17090.
15. Focosi D, Maggi F. Neutralising antibody escape of SARS-CoV-2 spike protein: risk assessment for antibody-based Covid-19 therapeutics and vaccines. Rev Med Virol. 2021;31:e2231. doi:10.1002/rmv.2231.
16. Starr TN, Greaney AJ, Dingens AS, et al. Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016. Cell Rep Med. 2021;2(4):100255.
17. Liu H, Wei P, Zhang Q, et al. 501Y.V2 and 501Y.V3 variants of SARS-CoV-2 lose binding to Bamlanivimab in vitro. MAbs. 2021;13(1):1919285. doi:10.1080/19420862.2021.1919285.
Keywords:

SARS-CoV-2; COVID-19; bamlanivimab; monoclonal antibody

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.